Venous thromboembolism (VTE), comprising deep venous thrombosis and pulmonary embolism, is a major contributor to morbidity and mortality in the U.S. We propose a 3-year renewal of the Longitudinal Investigation of Thromboembolism Etiology (LITE), a prospective study of VTE in the Atherosclerosis Risk in Communities (ARIC) Study and Cardiovascular Health Study (CHS) cohorts, involving 21,680 participants followed for more than two decades. In the previous four project periods, during which 1,055 VTEs occurred, we successfully identified or clarified, via 91 publications, multiple genetic and non-genetic risk factors for VTE. We plan to build upon these findings during this continuation, by adding VTE cases, addressing new hypotheses related to VTE risk factors or outcomes, and using the information from all project periods to improve understanding of VTE occurrence. LITE renewal aims are to: (1) Extend VTE event follow-up in ARIC for 4 more years, increasing the number of LITE VTE events by 262, to a total of 1,317. (2) Explore in depth possible reasons for the higher rates of VTE incidence in African Americans than whites, and systematically test for clinically relevant race interactions with risk factors for VTE. (3) Test the prospective association of incident VTE with novel biomarkers available at no additional cost: plasma galactin 3, sex hormones, and changes in plasma NT- proBNP, troponin T, and C-reactive protein. (4) Measure plasma high molecular weight kininogen and prekallikrein, components of the contact pathway of coagulation, and determine their association with VTE. (5) Test the prospective association of VTE with blood-based biomarkers of accelerated aging?shorter teleomere length and lower mitochontrial copy number. (6) Study the long-term consequences of VTE on physical functioning and quality of life. LITE is one of the few and most productive US prospective studies on VTE. A 3-year renewal will allow LITE to contribute new information on VTE risk factors and outcomes, with potential implications for VTE prevention and treatment.